Week 10: Infertility and pregnancy loss Flashcards
Define infertility
Failure to achieve pregnancy after 12 months of regular, unprotected intercourse or due to a person’s capacity to reproduce either as an individual or with their partner (irregular period, tubal surgery, no access to sperm/ovaries/uterus)
Evaluation for causes of infertility should be done when?
-Woman is 35yr+: evaluation should begin after 6 months of attempts
-Woman is 40+ or has a known impairment: immediately
Rank the non-genetic causes of infertility for couples from most to least common:
Unexplained
Ovulatory dysfunction
Tubal/pelvic pathology
Unusual problems
Male problems
- Male problems (35%) and tubal/pelvic pathology (35%)
- Ovulatory dysfunction (15%)
- Unexplained infertility (10%)
- Unusual problems
Rank the non-genetic causes of infertility for women from most to least common:
Unexplained
Tubal/pelvic pathology
Ovulatory dysfunction
Unusual problems
- Tubal/pelvic pathology (40%) and ovulatory dysfunction (40%)
- Unexplained (10%) and unusual problems (10%)
About how many eggs are women born with? About how many are left by puberty?
Start with ~1-2 million
~300-400K left by puberty
What tests are completed to assess ovarian reserve?
3 blood tests and a vaginal US:
-Anti-Mullerian hormone
-Day 3 FSH
-Day 3 estradiol
-Antral follicle count (AFC)
A higher AMH (anti-Mullerian hormone) means what?
A greater number of eggs left/higher ovarian reserve
Anovulation means what?
Irregular menstrual cycles or not ovulating
A normal menstrual cycle is how long?
21-35 days
What can be used to track ovulation? What is this test measuring?
Ovulation predictor kits (OPKs)
These kits measure LH level
What is the most common cause of anovulation?
PCOS
What is a tubal factor that can contribute to infertility?
Dilated tubes
-Not good
-Can put pressure on cilia which is important for egg movement from ovary to tube
-Typically recommended to remove dilated tubes
What are some uterine factors that can contribute to infertility?
-Submucosal fibroid
-Uterine polyps
-Interuterine adhesions: caused by infection or surgery/miscarriage which makes prone to scar tissue, surgery to remove
Name and explain male factors that contribute to infertility?
-Genetic
-Anatomic: varicoceles, previous surgeries
-Hormonal: low testosterone, high FSH
-Lifestyle factors: smoking cigs, alcohol intake, illicit drugs, obesity, psychological stress, APA, diet, caffeine intake
Name 5 infertility treatment options
- Ovulation induction
- IUI
- IVF with or without PGT
- Donor egg, sperm, embryo
- Gestational carrier
What two ARTs are considered “third party reproduction”?
-Donor egg, sperm, embryo
-Gestational carrier
Describe ovulation induction
-Use of medications that trick brain into producing FSH and boost ovulation (greater possibility for multiples)
-Meds include clomiphene citrate and Letrozole
-Injectable gonadotropins (stimulate ovaries)
-Trigger ovulation with hCG: body thinks that it’s the same as LH due to similar structure of protein and hCG has longer half life vs LH so can be more effective
Describe IUI
-Trouble getting sperms to swimming pool
-Sperm are washed and then placed into the uterus using a catheter
Describe IVF
-Embryos are created outside the body in lab
-Stimulation with injectable gonadotropins (FSH and LH)
-Oocyte retrieval
-Fertilization with intracytoplasmic sperm injection (ICSI)
-Embryo transfer
Define recurrent pregnancy loss
-The spontaneous loss of 2+ pregnancies
-Estimated that fewer than 5% of women will experience 2 consecutive losses and only 1% experience 3+
List 3 non genetic causes of RPL
- Antiphospholipid syndrome (APS)
- Anatomic
- Hormonal/metabolic
What are some hormonal causes of recurrent pregnancy loss?
-Uncontrolled diabetes: glycohemoglobin
-Hyperprolactinemia: prolactin
-Hypothyroidism: TSH
-Diminished ovarian reserve: AMH, day 3 FSH and estradiol
What is sperm DNA fragmentation?
refers to lesions, damage or breaks in the genetic material of the sperm, and is one of the major causes of male infertility
Sperm DNA fragmentation has been correlated with what related to pregnancy?
-More DNA breakage in sperm=longer time to get pregnant and more miscarriage
can filter/select out for this now
-Couples with unexplained RM had significantly increased levels of SDF and significantly decreased levels of total motility and progressive motility compared to couples without RM
-SDF assay may be considered for inclusion in evaluations of couples with unexplained RM
The majority of miscarriages are ___
Sporadic and thought to result from genetic causes that are greatly influenced by maternal age
Up to ___% of cases of RPL will not have a clearly defined etiology
50%
Infertility affects ___% of couples
10-15%
Recurrent pregnancy loss affects ___% of couples
1-5%
At how many weeks GA are developmental pathways activated that lead to development of gonads?
7wks
The female developmental pathway is largely hormone _____
Independent
The male development pathway is heavily hormone ____
Dependent
How does XXY contribute to male factor infertility?
-Abnormal development of testicles
-Arrest of spermatogenesis at primary spermatocyte stage
-Leads to azoospermia or oligospermia
-Leads to low testosterone production
-Mosaic Klinefelter typically have fewer infertility problems
What reproductive options are available for those with Klinefelter syndrome?
-Candidates for microscopic testicular sperm extraction (microTESE)
-IVF if desire biological offspring
-Consider PGTA: potential increased risk for embryos with sex chromosome aneuploidy
Describe how cystic fibrosis is considered a male factor of infertility
-Obstructive reason for infertility
->95% of males with CF have obstructive azoospermia: congenital bilateral absence vans deferens (CBAVD)
+Depends on type of CF
variant present
-Patients presenting sometimes not just regular CF but sometimes CFTR-related conditions
Describe Y chromosome microdeletion and how it relates to male factor infertility
-Deletion of AZF (azoospermia factor) region related to sperm production
-AZFa: Sertoli-cell only syndrome
-AZFb: arrest of spermatogenesis at primary spermatocyte stage
-AZFc: low sperm concentration and spermatogenesis
+Also more prone to smaller sub-dels and involvement of the DAZ gene
Why is it important to know the status of Y chromosome microdeletion?
Important to know for sperm retrieval surgery- know likelihood of sperm existing in the first place
How could ciliopathies contribute to male factor infertility?
Affect ability of sperm to swim
Describe how translocations could relate to male factor infertility
-Autosomal translocations: found in 4-10x more infertile males than fertile males
-Robertsonian translocations: most common type
Why it’s important to do karyotypes on BOTH partners undergoing fertility workup!
How is fragile X related to male factor infertility
-CGG repeat expansion in FMR1 gene
-FMR1 localizes primarily to the brain and testes, and is involved in cell-to-cell communication and nerve function
Other XY related factors for infertility
-Kennedy disease: CAG repeat expansion, the longer the repeat= the weaker the androgen receptor activity
-Androgen insensitivity syndrome: insensitivity to androgens, feminization of external genitalia and abnormal sex characteristics
-5-alpha reductase deficiency: reduced production of DHT leads to disruption of external male sex organ development
-X-linked adrenal hypoplasia congenita: shortage of male sex hormones
-Kallmann syndrome: hypothalamus doesn’t work properly, mutations in gene prevent puberty and lead to microphallus, undescended testes, (overlaping phenotype with other non-kallmann genes which is important to sus out because it affects repro risk and risk to children)
Lack of smell is symptomatic of which XY factor infertility syndrome?
Kallmann syndrome
Female sex development is largely _______ _______
Hormone independent
Females by default
How is Turner syndrome related to female factor infertility?
-Lack of second sex chromosome causes dosage compensation effects
-Streak ovaries/ovarian dysgenesis
-Amenorrhea
-Premature ovarian failure
-Lack of estrogen production!
How is Fragile X related to female factor infertility?
-Silenced FMR1 gene leads to toxic buildup of messenger RNA which effects ovarian function/menstruation
-Prolongs estrogen-deficient state
-POI
How is galactosemia related to female factor infertility?
-POI
-Exact cause uncertain, believed galactose or byproduct may be toxic to ovaries
How is polycystic ovarian syndrome related to female factor infertility?
-Cysts throw everything off
-Dysregulation
-Multifactorial things
Hormone replacement therapy is a viable treatment options for what 2 syndromes that contribute to infertility?
-Klinefelter: testosterone
-Turner: growth hormone and estrogen
Donor sperm/egg is a viable treatment option for bypassing what factors of infertility?
-Bypass CBAVD, azoospermia, oligozoospermia
-Bypass ovarian insufficiency/failure
Briefly outline the 7 steps of IVF
- Ovarian hyperstimulation
- Egg retrieval
- Sperm “donation”
- Fertilization
- Maturation
- Embryo transfer
- Implantation
Aided by intracytoplasmic sperm injection (ICSI)
How are cells accessed to test for PGT?
-Mature embryo at day 5-6 blastocyst stage (~70-200 cells)
-Rupture zone pellucida with micropipette and extract 5-10 cells)
-Run appropriate PGT
Name and briefly describe the four types of PGT
- PGT-A
-Aneuploidy, available to all IVF patients - PGT-M
-Monogenic conditions
-Disclosure vs nondisclosure (ie HD, don’t want to pass on but don’t want to know own status) - PGT-SR
-Inversions
-Translocations - PGT-P
-Polygenic risk scores, not commonly facilitated
Name the different types of 3rd party reproduction
-Sperm donor
-Egg donor
-Embryo donor
-Surrogate: biologically related/oocyte donor
-Gestational carrier: non-biological
Name some considerations for 3rd party reproductive options
-Carrier screening
-Financial ability
-Insurance coverage
-Support (family, friends, religion)
